PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis

Summary

This will be a randomized double blind placebo-controlled pilot study using a repeated measures design in which participants with acute ischemic stroke and intracranial atherosclerotic disease are randomized to either drug or placebo.

Timeline

Start

2018-10-30

Primary completion

2020-04-17

Completion

2020-04-17

Publications

• Background Suri MF, Johnston SC. Epidemiology of intracranial stenosis. J Neuroimaging. 2009 Oct;19 Suppl 1:11S-6S. doi: 10.1111/j.1552-6569.2009.00415.x.
• Background Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013 Nov;12(11):1106-14. doi: 10.1016/S1474-4422(13)70195-9.
• Background Arenillas JF. Intracranial atherosclerosis: current concepts. Stroke. 2011 Jan;42(1 Suppl):S20-3. doi: 10.1161/STROKEAHA.110.597278. Epub 2010 Dec 16.
• Background Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke. 2014 Jan;16(1):27-35. doi: 10.5853/jos.2014.16.1.27. Epub 2014 Jan 31.
• Background Koo J. The Latest Information on Intracranial Atherosclerosis: Diagnosis and Treatment. Interv Neurol. 2015 Oct;4(1-2):48-50. doi: 10.1159/000438779. Epub 2015 Sep 18.
• Background Wang YL, Pan YS, Zhao XQ, Wang D, Johnston SC, Liu LP, Meng X, Wang AX, Wang CX, Wang YJ; CHANCE investigators. Recurrent stroke was associated with poor quality of life in patients with transient ischemic attack or minor stroke: finding from the CHANCE trial. CNS Neurosci Ther. 2014 Dec;20(12):1029-35. doi: 10.1111/cns.12329. Epub 2014 Oct 13.
• Background Wang A, Wu L, Wang X, Zhao X, Wang C, Liu L, Zheng H, Cao Y, Wang Y, Wang Y; China National Stroke Registry investigators. Effect of recurrent stroke on poor functional outcome in transient ischemic attack or minor stroke. Int J Stroke. 2016 Oct;11(7):NP80. doi: 10.1177/1747493016641954. Epub 2016 Mar 24. No abstract available.
• Background Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. Circulation. 2011 May 17;123(19):2111-9. doi: 10.1161/CIRCULATIONAHA.109.934786. Epub 2011 May 2.
• Background Chaturvedi S, Sacco RL. How recent data have impacted the treatment of internal carotid artery stenosis. J Am Coll Cardiol. 2015 Mar 24;65(11):1134-43. doi: 10.1016/j.jacc.2014.12.045.
• Background Bonati LH, Dobson J, Featherstone RL, Ederle J, van der Worp HB, de Borst GJ, Mali WP, Beard JD, Cleveland T, Engelter ST, Lyrer PA, Ford GA, Dorman PJ, Brown MM; International Carotid Stenting Study investigators. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet. 2015 Feb 7;385(9967):529-38. doi: 10.1016/S0140-6736(14)61184-3. Epub 2014 Oct 14.
• Background Brott TG, Howard G, Roubin GS, Meschia JF, Mackey A, Brooks W, Moore WS, Hill MD, Mantese VA, Clark WM, Timaran CH, Heck D, Leimgruber PP, Sheffet AJ, Howard VJ, Chaturvedi S, Lal BK, Voeks JH, Hobson RW 2nd; CREST Investigators. Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis. N Engl J Med. 2016 Mar 17;374(11):1021-31. doi: 10.1056/NEJMoa1505215. Epub 2016 Feb 18.
• Background Paraskevas KI, Mikhailidis DP, Veith FJ, Spence JD. Definition of Best Medical Treatment in Asymptomatic and Symptomatic Carotid Artery Stenosis. Angiology. 2016 May;67(5):411-9. doi: 10.1177/0003319715624526. Epub 2015 Dec 31.
• Background Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, Sila CA, Jovin TG, Romano JG; Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005 Mar 31;352(13):1305-16. doi: 10.1056/NEJMoa043033.
• Background den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FL, van der Graaf Y, Algra A, de Borst GJ; SMART Study Group. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke. 2013 Apr;44(4):1002-7. doi: 10.1161/STROKEAHA.111.669267. Epub 2013 Feb 12.
• Background Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, Cates CU, Creager MA, Fowler SB, Friday G, Hertzberg VS, McIff EB, Moore WS, Panagos PD, Riles TS, Rosenwasser RH, Taylor AJ. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery DiseaseA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery Developed in Collaboration With the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2011 Feb 22;57(8):e16-e94.
• Background Windecker S, Stortecky S, Stefanini GG, da Costa BR, Rutjes AW, Di Nisio M, Silletta MG, Maione A, Alfonso F, Clemmensen PM, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head S, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter D, Schauerte P, Sousa Uva M, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A, Kolh P, Juni P. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ. 2014 Jun 23;348:g3859. doi: 10.1136/bmj.g3859.
• Background Pursnani S, Korley F, Gopaul R, Kanade P, Chandra N, Shaw RE, Bangalore S. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials. Circ Cardiovasc Interv. 2012 Aug 1;5(4):476-90. doi: 10.1161/CIRCINTERVENTIONS.112.970954. Epub 2012 Aug 7.
• Background de Havenon A, Yuan C, Tirschwell D, Hatsukami T, Anzai Y, Becker K, Sultan-Qurraie A, Mossa-Basha M. Nonstenotic Culprit Plaque: The Utility of High-Resolution Vessel Wall MRI of Intracranial Vessels after Ischemic Stroke. Case Rep Radiol. 2015;2015:356582. doi: 10.1155/2015/356582. Epub 2015 Aug 6.
• Background Kim JM, Jung KH, Sohn CH, Moon J, Shin JH, Park J, Lee SH, Han MH, Roh JK. Intracranial plaque enhancement from high resolution vessel wall magnetic resonance imaging predicts stroke recurrence. Int J Stroke. 2016 Feb;11(2):171-9. doi: 10.1177/1747493015609775.
• Background Gutierrez J, Elkind MS, Virmani R, Goldman J, Honig L, Morgello S, Marshall RS. A pathological perspective on the natural history of cerebral atherosclerosis. Int J Stroke. 2015 Oct;10(7):1074-80. doi: 10.1111/ijs.12496. Epub 2015 Apr 8.
• Background Mossa-Basha M, Hwang WD, De Havenon A, Hippe D, Balu N, Becker KJ, Tirschwell DT, Hatsukami T, Anzai Y, Yuan C. Multicontrast high-resolution vessel wall magnetic resonance imaging and its value in differentiating intracranial vasculopathic processes. Stroke. 2015 Jun;46(6):1567-73. doi: 10.1161/STROKEAHA.115.009037. Epub 2015 May 7.
• Background Teng Z, Peng W, Zhan Q, Zhang X, Liu Q, Chen S, Tian X, Chen L, Brown AJ, Graves MJ, Gillard JH, Lu J. An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery. Eur Radiol. 2016 Jul;26(7):2206-14. doi: 10.1007/s00330-015-4008-5. Epub 2015 Sep 16.
• Background Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951.
• Background Gupta A, Baradaran H, Al-Dasuqi K, Knight-Greenfield A, Giambrone AE, Delgado D, Wright D, Teng Z, Min JK, Navi BB, Iadecola C, Kamel H. Gadolinium Enhancement in Intracranial Atherosclerotic Plaque and Ischemic Stroke: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2016 Aug 15;5(8):e003816. doi: 10.1161/JAHA.116.003816.
• Background Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. AJR Am J Roentgenol. 2007 Mar;188(3):W223-32. doi: 10.2214/AJR.05.2027.
• Background de Havenon A, Chauhan N, Majersik J, Parker D, McNally. Determinants of Intracranial Atherosclerotic Enhancement on Vessel Wall MRI in Patients with Acute Ischemic Stroke. Houston, TX; 2017 [cited 2017 Feb 13]. Available from: http://www.abstractsonline.com/pp8/#!/4172/presentation/9649
• Background de Havenon A, Chauhan N, Kim S, Hadley J, Parker D, Majersik J, McNally S. Determinants of Symptomatic Intracranial Atherosclerotic Plaque Enhancement on 3D DANTE T1-SPACE Vessel Wall MRI and Relationship to Recurrent Stroke or TIA. Honolulu, HI; 2017.
• Background Hosseini AA, Kandiyil N, Macsweeney ST, Altaf N, Auer DP. Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. Ann Neurol. 2013 Jun;73(6):774-84. doi: 10.1002/ana.23876. Epub 2013 Jun 4.
• Background Wasserman BA, Wityk RJ, Trout HH 3rd, Virmani R. Low-grade carotid stenosis: looking beyond the lumen with MRI. Stroke. 2005 Nov;36(11):2504-13. doi: 10.1161/01.STR.0000185726.83152.00. Epub 2005 Oct 20.
• Background Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, Dunning A, Mushlin AI, Sanelli PC. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke. 2013 Nov;44(11):3071-7. doi: 10.1161/STROKEAHA.113.002551. Epub 2013 Aug 29.
• Background McNally JS, Kim SE, Mendes J, Hadley JR, Sakata A, De Havenon AH, Treiman GS, Parker DL. Magnetic Resonance Imaging Detection of Intraplaque Hemorrhage. Magn Reson Insights. 2017 Mar 7;10:1-8. doi: 10.1177/1178623X17694150. eCollection 2017.
• Background Diagnostic Radiology: Magnetic Resonance Imaging (MRI) Practice Parameters and Technical Standards - American College of Radiology [Internet]. [cited 2015 Jan 30]. Available from: http://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/MRI
• Background de Havenon, A, Chung L, Park, M, Mossa-Basha, M. Intracranial vessel wall MRI: a review of current indications and future applications. Neurovascular Imaging. 2016;2(10).
• Background Stroke Standards - NINDS Common Data Elements [Internet]. [cited 2015 Jan 3]. Available from: http://www.commondataelements.ninds.nih.gov/stroke.aspx#tab=Data_Standards
• Background Mandell DM, Mossa-Basha M, Qiao Y, Hess CP, Hui F, Matouk C, Johnson MH, Daemen MJ, Vossough A, Edjlali M, Saloner D, Ansari SA, Wasserman BA, Mikulis DJ; Vessel Wall Imaging Study Group of the American Society of Neuroradiology. Intracranial Vessel Wall MRI: Principles and Expert Consensus Recommendations of the American Society of Neuroradiology. AJNR Am J Neuroradiol. 2017 Feb;38(2):218-229. doi: 10.3174/ajnr.A4893. Epub 2016 Jul 28.
• Background Scott McNally J, Yoon HC, Kim SE, Narra KK, McLaughlin MS, Parker DL, Treiman GS. Carotid MRI Detection of Intraplaque Hemorrhage at 3T and 1.5T. J Neuroimaging. 2015 May-Jun;25(3):390-6. doi: 10.1111/jon.12146. Epub 2014 Jul 15.
• Background van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, Inzitari D, Waldemar G, Erkinjuntti T, Mantyla R, Wahlund LO, Barkhof F; LADIS Group. Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke. 2006 Mar;37(3):836-40. doi: 10.1161/01.STR.0000202585.26325.74. Epub 2006 Jan 26.
• Background Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, Sullivan M, Horowitz KR, Ding J, Marcovina S, Lovato LC, Lovato J, Margolis KL, O'Connor P, Lipkin EW, Hirsch J, Coker L, Maldjian J, Sunshine JL, Truwit C, Davatzikos C, Bryan RN; ACCORD MIND investigators. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011 Nov;10(11):969-77. doi: 10.1016/S1474-4422(11)70188-0. Epub 2011 Sep 28.
• Background SNOMED Clinical Terms® (SNOMED CT®) [Internet]. [cited 2015 Jan 3]. Available from: http://www.nlm.nih.gov/research/umls/Snomed/snomed_main.html

Drugs

Indications